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Urothelial Bladder Carcinoma Study

What is urothelial bladder cancer?

Urothelial bladder cancer is the most common type of bladder cancer. The bladder is a hollow organ that holds liquid waste, or urine, produced by the kidneys. Invasive bladder cancer develops in the inner lining of the bladder wall and grows finger-like projections, called papillary tumors, into the hollow part of the bladder. In 2010, it was estimated that 70,500 people would be diagnosed with bladder cancer and an estimated 15,000 would die from from the disease.1 Urothelial bladder cancer is more common among men than women. From 2003 to 2007, the median age of death from bladder cancer was 78 years of age. If the cancer is diagnosed after it has metastasized, as few as 5% of patients will be living five years after diagnosis. Additional information on urothelial bladder cancer.

What have TCGA researchers learned about urothelial bladder cancer?

  • 64 significantly mutated genes were identified from the tumors studied.
  • Altered signaling pathways and protein expression include: p53/cell cycle, DNA repair, PI3K/AKT, and chromatin modifications and regulation. Many of these alterations may have applicable therapies currently under development that should be further investigated:
    • Tumors with p53/cell cycle alterations may benefit from drugs targeting the cell cycle, such as palbocicilib.
    • Tumors harboring multiple mutations consistent with an upstream alteration to the APOBEC family of enzymes, a known cancer signature, should be further investigated to better understand the patient immune reaction and if immune checkpoint therapy may apply.
    • Tumors with chromatin modifier gene mutations could benefit from drugs affecting histone acetylation and deacetylation, such as BET and EZH2 inhibitors.
    • Samples with elevated HER2 protein expression may respond to HER2 directed treatments, such as Herceptin and T-DMI.
  • Multiple subtypes of muscle-invasive bladder cancer exist, each with unique underlying molecular characteristics and potential treatment strategies:
    • The luminal-papillary subtype has a lower risk of progression and a lower likelihood of response to cisplatin-based neoadjuvant chemotherapy (NAC). Instead, tyrosine kinase inhibitors of FGFR3 may be worth investigating.
    • The luminal-infiltrated subtype resembles a previously TCGA-established cancer subtype known to respond to immune checkpoint therapy with atezolizumab. This subtype may also be resistant to cisplatin-based chemotherapy.
    • The luminal subtype, more distinct from previously established subtypes, may respond to NAC and requires further research to identify an appropriate targeted therapy.
    • The basal-squamous subtype shows signs of immune infiltration and may benefit from immune checkpoint therapy or cisplatin-based NAC.
    • The neuronal subtype may behave similarly to neuroendocrine neoplasms of other tissue sites and may respond to etoposide-cisplatin therapy.
  • Smoking is strongly associated with bladder cancer, as over half of tumors were from patients with a history of smoking.
    • Smokers had a higher incidence of both mutations in the ERCC2 gene and the ERCC2 mutation signature, or a panel of mutations that tend to occur after a mutation in the ERCC2 gene.